ClinVar Miner

Submissions for variant NM_001042492.3(NF1):c.654+1G>T

dbSNP: rs1060500245
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000464166 SCV000541968 pathogenic Neurofibromatosis, type 1 2020-01-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NF1 are known to be pathogenic (PMID: 10712197, 23913538). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with clinical features of neurofibromatosis type-1 (NF1) and/or NF1-Noonan syndrome (PMID: 21354044, Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 6 of the NF1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product.
Ambry Genetics RCV002356635 SCV001187569 likely pathogenic Hereditary cancer-predisposing syndrome; Cardiovascular phenotype 2018-10-10 criteria provided, single submitter clinical testing The c.654+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the NF1 gene. This mutation has been identified in an individual meeting diagnostic criteria for neurofibromatosis type 1 (NF1); authors performed RNA studies, which reportedly showed that this variant causes exon 6 skipping and a resultant truncated protein (Valero MC et al. J Mol Diagn 2011 Mar;13(2):113-22). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. In addition to the published literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
3billion RCV000464166 SCV002318597 pathogenic Neurofibromatosis, type 1 2022-03-22 criteria provided, single submitter clinical testing Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant.It is not observed in the gnomAD v2.1.1 dataset. The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000404420). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome-Nilou Lab RCV000464166 SCV002561592 pathogenic Neurofibromatosis, type 1 2022-03-15 criteria provided, single submitter clinical testing
Baylor Genetics RCV003463843 SCV004199027 pathogenic Juvenile myelomonocytic leukemia 2021-04-30 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.